Fludarabine Followed by Alemtuzumab Produces High Response Rates in Previously Untreated CLL

Fludarabine Followed by Alemtuzumab Produces High Response Rates in Previously Untreated CLL

NEW HYDE PARK, New
York-Single-agent fludarabine (Fludara)
is an active front-line therapy
for chronic lymphocytic leukemia
(CLL) and has resulted in overall response
rates of 63% to 71%.[1,2]
Slightly higher response rates (approximately
87%) in previously untreated
patients with CLL have been reported
for subcutaneous alemtuzumab
(Campath-1H), an anti-CD52
monoclonal antibody.[3] As part of
the ongoing quest to improve response
rates for patients with CLL,
the Cancer and Leukemia Group B
(CALGB) conducted a study using
sequential administration of fludarabine
followed by alemtuzumab.
Kanti R. Rai, MD, of Long Island
Jewish Medical Center, Albert Einstein
College of Medicine, New Hyde
Park, New York, presented results of
the phase II trial (ASH abstract
772).[4] The primary goal of the study
was to determine the toxicity and response
rates of fludarabine plus alemtuzumab
in treatment-naive patients
with CLL.
Patients were administered fludarabine
25 mg/m2 per day intravenously
for 5 days and monthly thereafter for
4 months. Those who achieved stable
disease or better were then treated
with a 6-week course of alemtuzumab
30 mg three times per week intravenously,
with the antibody first given at
3 mg, then progressively increased as
tolerated during the first week, up to
30 mg. Patients were also treated with
prophylactic trimethoprim-sulfamethoxazole
double strength (DS)
and acyclovir (Zovirax) during and
for 6 months after alemtuzumab therapy.
Final response results were evaluated
2 months after completion of
therapy.
Effective as Combination
A total of 57 patients were enrolled
in the trial. One patient died before
initiation of fludarabine therapy; safety
and efficacy evaluations are therefore
based on 56 patients. During fludarabine
therapy, 11 patients required
parenteral antibiotics and/or hospitalization
for serious infections, and 1
patient died of septicemia. After fludarabine
therapy, three (5%) patients
achieved a complete response and 28
(50%) achieved a partial response. Of
the 56 patients who received fludarabine,
17 were not treated with alemtuzumab
either because of no response
(7 patients) or progressive disease (10
patients). Thus, 39 patients received
alemtuzumab and were evaluable for
response.
The combination of alemtuzumab
and fludarabine proved highly effective.
The overall response rate among
39 patients who received alemtuzumab
was 92% (36 patients), including a
36% complete response rate and 56%
partial response rate, according to
National Cancer Institute-Working
Group 1996 criteria.
Among the 56 intent-to-treat patients
enrolled in the study, the complete
response rate was 25% and the
partial response rate was 40%. Of
the 12 patients who had stable disease
after fludarabine treatment, two
(17%) achieved a complete response
after alemtuzumab therapy. After a
median follow-up of 10 months, 87%
of the 56 intent-to-treat patients were
still alive.
Improved CMV Recognition
Alemtuzumab infusion reactions
were manageable and in most cases
were limited to grade 1 or 2. Twelve
patients had grade 3 or higher infections
requiring parenteral antibiotics
or hospitalization.
Infection with cytomegalovirus
(CMV) occurred in eight patients during
or within 4 months of alemtuzumab
therapy. Complete or partial
resolution of CMV occurred in six of
these patients. Persistent CMV occurred
in one patient, and one patient
died. Following the fatality, weekly
qualitative polymerase chain reactionbased
testing for CMV was initiated
to improve early recognition of CMV
and to allow both discontinuation of
alemtuzumab and initiation of antiviral
therapy.
These results compare favorably
with those of a similar trial conducted
with sequential fludarabine and ritdarabine,
uximab (Rituxan).[5] In that trial, 53
previously untreated CLL patients received
6 monthly courses of fludarabine
followed 2 months later with
rituximab. The overall response rate
with sequential administration of fludarabine
and rituximab was 77% (41
patients), including 28% complete
and 49% partial response rates (95%
confidence interval, 0.66, 0.89).
Although these early results with
alemtuzumab in combination with
fludarabine are encouraging, Dr. Rai
cautioned that longer follow-up will
be necessary to determine whether
alemtuzumab has a positive influence
on survival in patients who have received
initial therapy with fludarabine.